Investigating brain dynamics and their association with cognitive control in opioid use disorder using naturalistic and drug cue paradigms.

Objectives: Opioid use disorder (OUD) impacts millions of people worldwide. The prevalence and debilitating effects of OUD present a pressing need to understand its neural mechanisms to provide more targeted interventions. Prior studies have linked altered functioning in large-scale brain networks with clinical symptoms and outcomes in OUD. However, these investigations often do not consider how brain responses change over time. Time-varying brain network engagement can convey clinically relevant information not captured by static brain measures. Methods: We investigated brain dynamic alterations in individuals with OUD by applying a new multivariate computational framework to movie-watching (i.e., naturalistic; N=76) and task-based (N=70) fMRI. We further probed the associations between cognitive control and brain dynamics during a separate drug cue paradigm in individuals with OUD. Results: Compared to healthy controls (N=97), individuals with OUD showed decreased variability in the engagement of recurring brain states during movie-watching. We also found that worse cognitive control was linked to decreased variability during the rest period when no opioid-related stimuli were present. Conclusions: These findings suggest that individuals with OUD may experience greater difficulty in effectively engaging brain networks in response to evolving internal or external demands. Such inflexibility may contribute to aberrant response inhibition and biased attention toward opioid-related stimuli, two hallmark characteristics of OUD. By incorporating temporal information, the current study introduces novel information about how brain dynamics are altered in individuals with OUD and their behavioral implications.

Brain-phenotype models fail for individuals who defy sample stereotypes.

Individual differences in brain functional organization track a range of traits, symptoms and behaviours1-12. So far, work modelling linear brain-phenotype relationships has assumed that a single such relationship generalizes across all individuals, but models do not work equally well in all participants13,14. A better understanding of in whom models fail and why is crucial to revealing robust, useful and unbiased brain-phenotype relationships. To this end, here we related brain activity to phenotype using predictive models-trained and tested on independent data to ensure generalizability15-and examined model failure. We applied this data-driven approach to a range of neurocognitive measures in a new, clinically and demographically heterogeneous dataset, with the results replicated in two independent, publicly available datasets16,17. Across all three datasets, we find that models reflect not unitary cognitive constructs, but rather neurocognitive scores intertwined with sociodemographic and clinical covariates; that is, models reflect stereotypical profiles, and fail when applied to individuals who defy them. Model failure is reliable, phenotype specific and generalizable across datasets. Together, these results highlight the pitfalls of a one-size-fits-all modelling approach and the effect of biased phenotypic measures18-20 on the interpretation and utility of resulting brain-phenotype models. We present a framework to address these issues so that such models may reveal the neural circuits that underlie specific phenotypes and ultimately identify individualized neural targets for clinical intervention.

Structural and functional brain changes in hepatic and neurological Wilson disease.

Wilson disease (WD) can manifest with hepatic or neuropsychiatric symptoms. Our understanding of the in vivo brain changes in WD, particularly in the hepatic phenotype, is limited. Thirty subjects with WD and 30 age- and gender-matched controls participated. WD group underwent neuropsychiatric assessment. Unified WD Rating Scale neurological exam scores were used to determine neurological (WDN, score > 0) and hepatic-only (WDH, score 0) subgroups. All subjects underwent 3 Tesla anatomical and resting-state functional MRI. Diffusion tensor imaging (DTI) and susceptibility-weighted imaging (SWI) were performed only in the WD group. Volumetric, DTI, and functional connectivity analyses were performed to determine between-group differences. WDN and WDH groups were matched in demographic and psychiatric profiles. The entire WD group compared to controls showed significant thinning in the bilateral superior frontal cortex. The WDN group compared to control and WDH groups showed prominent structural brain changes including significant striatal and thalamic atrophy, more subcortical hypointense lesions on SWI, and diminished white matter integrity in the bilateral anterior corona radiata and corpus callosum. However, the WDH group also showed significant white matter volume loss compared to controls. The functional connectivity between the frontostriatal nodes was significantly reduced in the WDN group, whereas that of the hippocampus was significantly increased in the WDH group compared to controls. In summary, structural and functional brain changes were present even in neurologically non-manifesting WD patients in this cross-sectional study. Longitudinal brain MRI scans may be useful as biomarkers for prognostication and optimization of treatment strategies in WD.

Altered Brain Response to Drinking Glucose and Fructose in Obese Adolescents.

Increased sugar-sweetened beverage consumption has been linked to higher rates of obesity. Using functional MRI, we assessed brain perfusion responses to drinking two commonly consumed monosaccharides, glucose and fructose, in obese and lean adolescents. Marked differences were observed. In response to drinking glucose, obese adolescents exhibited decreased brain perfusion in brain regions involved in executive function (prefrontal cortex [PFC]) and increased perfusion in homeostatic appetite regions of the brain (hypothalamus). Conversely, in response to drinking glucose, lean adolescents demonstrated increased PFC brain perfusion and no change in perfusion in the hypothalamus. In addition, obese adolescents demonstrated attenuated suppression of serum acyl-ghrelin and increased circulating insulin level after glucose ingestion; furthermore, the change in acyl-ghrelin and insulin levels after both glucose and fructose ingestion was associated with increased hypothalamic, thalamic, and hippocampal blood flow in obese relative to lean adolescents. Additionally, in all subjects there was greater perfusion in the ventral striatum with fructose relative to glucose ingestion. Finally, reduced connectivity between executive, homeostatic, and hedonic brain regions was observed in obese adolescents. These data demonstrate that obese adolescents have impaired prefrontal executive control responses to drinking glucose and fructose, while their homeostatic and hedonic responses appear to be heightened. Thus, obesity-related brain adaptations to glucose and fructose consumption in obese adolescents may contribute to excessive consumption of glucose and fructose, thereby promoting further weight gain.

Altered functional connectivity in seizure onset zones revealed by fMRI intrinsic connectivity.

OBJECTIVE: The purpose of this study was to investigate functional connectivity (FC) changes in epileptogenic networks in intractable partial epilepsy obtained from resting-state fMRI by using intrinsic connectivity contrast (ICC), a voxel-based network measure of degree that reflects the number of connections to each voxel. METHODS: We measured differences between intrahemispheric- and interhemispheric-ICC (ICCintra-inter) that could reveal localized connectivity abnormalities in epileptogenic zones while more global network changes would be eliminated when subtracting these values. The ICCintra-inter map was compared with the seizure onset zone (SOZ) based on intracranial EEG (icEEG) recordings in 29 patients with at least 1 year of postsurgical follow-up. Two independent reviewers blindly interpreted the icEEG and fMRI data, and the concordance rates were compared for various clinical factors. RESULTS: Concordance between the icEEG SOZ and ICCintra-inter map was observed in 72.4% (21/29) of the patients, which was higher in patients with good surgical outcome, especially in those patients with temporal lobe epilepsy (TLE) or lateral temporal seizure localization. Concordance was also better in the extratemporal lobe epilepsy than the TLE group. In 85.7% (18/21) of the cases, the ICCintra-inter values were negative in the SOZ, indicating decreased FC within the epileptic hemisphere relative to between hemispheres. CONCLUSIONS: Assessing alterations in FC using fMRI-ICC map can help localize the SOZ, which has potential as a noninvasive presurgical diagnostic tool to improve surgical outcome. In addition, the method reveals that, in focal epilepsy, both intrahemispheric- and interhemispheric-FC may be altered, in the presence of both regional as well as global network abnormalities.

Effects of fructose vs glucose on regional cerebral blood flow in brain regions involved with appetite and reward pathways.

IMPORTANCE: Increases in fructose consumption have paralleled the increasing prevalence of obesity, and high-fructose diets are thought to promote weight gain and insulin resistance. Fructose ingestion produces smaller increases in circulating satiety hormones compared with glucose ingestion, and central administration of fructose provokes feeding in rodents, whereas centrally administered glucose promotes satiety. OBJECTIVE: To study neurophysiological factors that might underlie associations between fructose consumption and weight gain. DESIGN, SETTING, AND PARTICIPANTS: Twenty healthy adult volunteers underwent 2 magnetic resonance imaging sessions at Yale University in conjunction with fructose or glucose drink ingestion in a blinded, random-order, crossover design. MAIN OUTCOME MEASURES: Relative changes in hypothalamic regional cerebral blood flow (CBF) after glucose or fructose ingestion. Secondary outcomes included whole-brain analyses to explore regional CBF changes, functional connectivity analysis to investigate correlations between the hypothalamus and other brain region responses, and hormone responses to fructose and glucose ingestion. RESULTS: There was a significantly greater reduction in hypothalamic CBF after glucose vs fructose ingestion (-5.45 vs 2.84 mL/g per minute, respectively; mean difference, 8.3 mL/g per minute [95% CI of mean difference, 1.87-14.70]; P = .01). Glucose ingestion (compared with baseline) increased functional connectivity between the hypothalamus and the thalamus and striatum. Fructose increased connectivity between the hypothalamus and thalamus but not the striatum. Regional CBF within the hypothalamus, thalamus, insula, anterior cingulate, and striatum (appetite and reward regions) was reduced after glucose ingestion compared with baseline (P < .05 significance threshold, family-wise error [FWE] whole-brain corrected). In contrast, fructose reduced regional CBF in the thalamus, hippocampus, posterior cingulate cortex, fusiform, and visual cortex (P < .05 significance threshold, FWE whole-brain corrected). In whole-brain voxel-level analyses, there were no significant differences between direct comparisons of fructose vs glucose sessions following correction for multiple comparisons. Fructose vs glucose ingestion resulted in lower peak levels of serum glucose (mean difference, 41.0 mg/dL [95% CI, 27.7-54.5]; P < .001), insulin (mean difference, 49.6 µU/mL [95% CI, 38.2-61.1]; P < .001), and glucagon-like polypeptide 1 (mean difference, 2.1 pmol/L [95% CI, 0.9-3.2]; P = .01). CONCLUSION AND RELEVANCE: In a series of exploratory analyses, consumption of fructose compared with glucose resulted in a distinct pattern of regional CBF and a smaller increase in systemic glucose, insulin, and glucagon-like polypeptide 1 levels.

Ipsilateral synkinesia involves the supplementary motor area.

The supplementary motor area coordinates movements. Synkinesia is a rare disorder in which an involuntary movement occurs coordinated with a voluntary movement. Here, we test the hypothesis that the supplementary motor area is involved in involuntary coordination of movement. We collected functional magnetic resonance imaging (fMRI) data from two patients with ipsilateral hand-foot synkinesia and two control participants while they performed rhythmic tasks. In synkinesia patients, both the supplementary motor area and the foot motor cortex were significantly activated during the hand motor task. This pattern was not seen in controls. Our findings suggest that the supplementary motor area plays a central role in involuntary coordination observed in synkinesia, and provides insight into how the supplementary motor area orchestrates movements.

BOLD response to semantic and syntactic processing during hypoglycemia is load-dependent.

This study investigates how syntactic and semantic load factors impact sentence comprehension and BOLD signal under moderate hypoglycemia. A dual session, whole brain fMRI study was conducted on 16 healthy participants using the glucose clamp technique. In one session, they experienced insulin-induced hypoglycemia (plasma glucose at ∼50mg/dL); in the other, plasma glucose was maintained at euglycemic levels (∼100mg/dL). During scans subjects were presented with sentences of contrasting syntactic (embedding vs. conjunction) and semantic (reversibility vs. irreversibility) load. Semantic factors dominated the overall load effects on both performance (p<0.001) and BOLD response (p<0.01, corrected). Differential BOLD signal was observed in frontal, temporal, temporo-parietal and medio-temporal regions. Hypoglycemia and syntactic factors significantly impacted performance (p=0.002) and BOLD response (p<0.01, corrected) in the reversible clause conditions, more extensively in reversible-embedded than in reversible-conjoined clauses. Hypoglycemia resulted in a robust decrease in performance on reversible clauses and exerted attenuating effects on BOLD unselectively across cortical circuits. The dominance of reversibility in all measures underscores the distinction between the syntactic and semantic contrasts. The syntactic is based in a quantitative difference in algorithms interpreting embedded and conjoined structures. We suggest that the semantic is based in a qualitative difference between algorithmic mapping of arguments in reversible clauses and heuristic linking in irreversible clauses. Because heuristics drastically reduce resource demand, the operations they support would resist the load-dependent cognitive consequences of hypoglycemia.

Social network theory applied to resting-state fMRI connectivity data in the identification of epilepsy networks with iterative feature selection.

Epilepsy is a brain disorder usually associated with abnormal cortical and/or subcortical functional networks. Exploration of the abnormal network properties and localization of the brain regions involved in human epilepsy networks are critical for both the understanding of the epilepsy networks and planning therapeutic strategies. Currently, most localization of seizure networks come from ictal EEG observations. Functional MRI provides high spatial resolution together with more complete anatomical coverage compared with EEG and may have advantages if it can be used to identify the network(s) associated with seizure onset and propagation. Epilepsy networks are believed to be present with detectable abnormal signatures even during the interictal state. In this study, epilepsy networks were investigated using resting-state fMRI acquired with the subjects in the interictal state. We tested the hypothesis that social network theory applied to resting-state fMRI data could reveal abnormal network properties at the group level. Using network data as input to a classification algorithm allowed separation of medial temporal lobe epilepsy (MTLE) patients from normal control subjects indicating the potential value of such network analyses in epilepsy. Five local network properties obtained from 36 anatomically defined ROIs were input as features to the classifier. An iterative feature selection strategy based on the classification efficiency that can avoid 'over-fitting' is proposed to further improve the classification accuracy. An average sensitivity of 77.2% and specificity of 83.86% were achieved via 'leave one out' cross validation. This finding of significantly abnormal network properties in group level data confirmed our initial hypothesis and provides motivation for further investigation of the epilepsy process at the network level.

Arterial transit time effects in pulsed arterial spin labeling CBF mapping: insight from a PET and MR study in normal human subjects.

Arterial transit time (ATT), a key parameter required to calculate absolute cerebral blood flow in arterial spin labeling (ASL), is subject to much uncertainty. In this study, ASL ATTs were estimated on a per-voxel basis using data measured by both ASL and positron emission tomography in the same subjects. The mean ATT increased by 260 +/- 20 (standard error of the mean) ms when the imaging slab shifted downwards by 54 mm, and increased from 630 +/- 30 to 1220 +/- 30 ms for the first slice, with an increase of 610 +/- 20 ms over a four-slice slab when the gap between the imaging and labeling slab increased from 20 to 74 mm. When the per-slice ATTs were employed in ASL cerebral blood flow quantification and the in-slice ATT variations ignored, regional cerebral blood flow could be significantly different from the positron emission tomography measures. ATT also decreased with focal activation by the same amount for both visual and motor tasks (approximately 80 ms). These results provide a quantitative relationship between ATT and the ASL imaging geometry and yield an assessment of the assumptions commonly used in ASL imaging. These findings should be considered in the interpretation of, and comparisons between, different ASL-based cerebral blood flow studies. The results also provide spatially specific ATT data that may aid in optimizing the ASL imaging parameters.

Language lateralization in epilepsy patients: fMRI validated with the Wada procedure.

PURPOSE: This work examines the efficacy of functional magnetic resonance imaging (fMRI) for language lateralization using a comprehensive three-task language-mapping approach. Two localization methods and four different metrics for quantifying activation within hemisphere are compared and validated with Wada testing. Sources of discordance between fMRI and Wada lateralization are discussed with respect to specific patient examples. METHODS: fMRI language mapping was performed in patients with epilepsy (N = 40) using reading sentence comprehension, auditory sentence comprehension, and a verbal fluency task. This was compared with the Wada procedure using both whole-brain and midline exclusion-based analyses. Different laterality scores were examined as a function of statistical threshold to investigate the sensitivity to threshold effects. RESULTS: For the lateralized patients categorized by Wada, fMRI laterality indices (LIs) were concordant with the Wada procedure results in 83.87% patients for the reading task, 83.33% patients for the auditory task, 76.92% patients for the verbal fluency task, and in 91.3% patients for the conjunction analysis. The patients categorized as bilateral via the Wada procedure showed some hemispheric dominance in fMRI, and discrepancies between the Wada test findings and the functional laterality scores arose for a range of reasons. DISCUSSION: Discordance was dependent upon whether whole-brain or midline exclusion method-based lateralization was calculated, and in the former case the inclusion of the occipital and other midline regions often negatively influenced the lateralization scores. Overall fMRI was in agreement with the Wada test in 91.3% of patients, suggesting its utility for clinical use with the proper consideration given to the confounds discussed in this work.

Small decrements in systemic glucose provoke increases in hypothalamic blood flow prior to the release of counterregulatory hormones.

OBJECTIVE: The hypothalamus is the central brain region responsible for sensing and integrating responses to changes in circulating glucose. The aim of this study was to determine the time sequence relationship between hypothalamic activation and the initiation of the counterregulatory hormonal response to small decrements in systemic glucose. RESEARCH DESIGN AND METHODS: Nine nondiabetic volunteers underwent two hyperinsulinemic clamp sessions in which pulsed arterial spin labeling was used to measure regional cerebral blood flow (CBF) at euglycemia ( approximately 95 mg/dl) on one occasion and as glucose levels were declining to a nadir of approximately 50 mg/dl on another occasion. Plasma glucose and counterregulatory hormones were measured during both study sessions. RESULTS: CBF to the hypothalamus significantly increased when glucose levels decreased to 77.2 +/- 2 mg/dl compared with the euglycemic control session when glucose levels were 95.7 +/- 3 mg/dl (P = 0.0009). Hypothalamic perfusion was significantly increased before there was a significant elevation in counterregulatory hormones. CONCLUSIONS: Our data suggest that the hypothalamus is exquisitely sensitive to small decrements in systemic glucose levels in healthy, nondiabetic subjects and that hypothalamic blood flow, and presumably neuronal activity, precedes the rise in counterregulatory hormones seen during hypoglycemia.

Detecting change in BOLD signal between sessions for atlas-based anatomical ROIs.

An algorithm using pre-defined regions of interest (ROIs) to detect differences between sessions in Blood Oxygen-Level Dependent (BOLD) signal is proposed and results from a reproducibility study are reported here. It is important to know whether tests for change have the desired statistical properties, e.g., low variability between sessions and unbiased false-positive rates, under null conditions so one is confident in any conclusions based on the metric and test used. This study examined three cognitive tasks: Stroop, response inhibition, Sternberg digits, and a visually-cued finger tapping task, in 20 healthy subjects. Each subject had two fMRI sessions, one week apart. A series of ROI summaries was constructed by choosing different proportions of voxels from the ROI and calculating the mean of t values for the selected voxels. The choice of voxels was based on the magnitude of the t values, selecting the maximum value, then the top 1%, and so on until all voxels in the ROI were included. No ROIs were found to have significant differences between sessions based on paired comparison t tests. Generally, the observed false-positive rates were near the expected rates for all summaries and tasks, although the Sternberg and Response Inhibition tasks did have higher false-positive rates when alpha>/= 0.1 for some ROI summaries. This study indicates results are reproducible and also have the desired statistical properties under null conditions.